The JAK kinase family is a cytoplasmic protein kinase family comprising the members JAK1, JAK2, JAK3, and TYK2. Growth factor or cytokine receptors that recruit JAK kinases include the interferon receptors, interleukin receptors (receptors for the cytokines IL-2 to IL-7, IL-9 to IL-13, IL-15, IL-23), various hormone receptors (erythropoietin (Epo) receptor, the thrombopoietin (Tpo) receptor, the leptin receptor, the insulin receptor, the prolactin (PRL) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, the growth hormone receptor, receptor protein tyrosine kinases (such as EGFR and PDGFR), and receptors for other growth factors (leukemia inhibitory factor (LIF), oncostatin M (OSM), IFNα/β/γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1)). See, Rane and Reddy, Oncogene 2000, 19, 5662-5679.
Phosphorylated receptors serve as docking sites for other SH-2 domain containing signaling molecules that interact with JAKs, such as the STAT family of transcription factors, Src family of kinases, MAP kinases, PI3 kinase, and protein tyrosine phosphatases (Rane and Reddy, Oncogene 2000, 19, 5662-5679). The family of latent cytoplasmic transcription factors, STATs, is the most well characterized downstream substrates for JAKs. The STAT proteins bind to phosphorylated cytokine receptors through their SH2 domains to become phosphorylated by JAKs, which leads to their dimerization, release, and eventual translocation to the nucleus where they activate gene transcription. The various members of STAT which have been identified thus far are STAT1, STAT2, STAT3, STAT4, STAT5 (including STAT5a and STAT5b), and STATE.
Since the JAK kinases may play an important signaling role via such receptors, disorders of fat metabolism, growth disorders and disorders of the immune system are all potential therapeutic targets.
The JAK kinases and JAK2 mutations are implicated in myeloproliferative disorders, cancers, including blood borne and solid tumors. Exemplary disorders include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML) and systemic mastocytosis (SM). Myeloproliferative disorders are believed to arise from either gain-of-function mutations to JAK itself or from activation by the oncoprotein BCR-ABL, which specifically activates the JAK2 pathway. Several literature reports describe role of JAK2 mutations in various disorders. See, Samanta et al., Cancer Res. 2006, 66, 6468-6472; Sawyers et al., Cell 1992, 70, 901-910; Tefferi, N. Eng. J. Med. 2007, 356, 444-445; Baxter et al., Lancet 2005, 365, 1054-1056; Jones et al., Blood 2005, 106, 2162-2168; Levine et al., Blood 2006, 107, 4139-4141; Campbell et al., Blood 2006, 107, 2098-2100; Scott et al., N. Eng. J. Med. 2007, 356, 459-468; Mercher et al., Blood 2006, 108, 2770-2778; Lacronique et al., Science 1997, 278, 1309-1312; Lacronique et al., Blood 2000, 95, 2535-2540; Griesinger et al., Genes Chromosomes Cancer 2005, 44, 329-333; Bousquet et al., Oncogene 2005, 24, 7248-7252; Schwaller et al., Mol. Cell. 2000 6, 693-704; and Zhao et al., EMBO 2002, 21, 2159-2167.
Literature indicates that JAK may also serve as a target for prostate cancer, including androgen-resistant prostate cancer. See, Barton et al., Mol. Canc. Ther. 2004, 3, 11-20, Blume-Jensen et al., Nature 2001, 411, 355-356; Bromberg, J. Clin. Invest. 2002, 109, 1139-1142; and Rane, Oncogene 2000, 19, 5662-5679. JAK as a prominent mediator of the cytokine signaling pathway is considered to be a therapeutic target for inflammation and transplant rejections. See, Borie et al., Transplantation 2005, 79, 791-801; and Milici et al., Arthritis Research 2008, 10, 1-9.
Given the multitude of diseases attributed to the dysregulation of JAK signaling, many small molecule inhibitors of JAK are currently being developed. Examples of compounds in preclinical development include TG101209 (TargeGen), and examples of compounds being investigated in clinical studies include INCB018424 (Incyte), XL019 (Exelixis), and TG101348 (TargeGen). See, Pardanani et al., Leukemia 2007, 21, 1658-1668; and Pardanai, Leukemia 2008, 22, 23-20.
There is, however, an existing need for a compound that is useful as a JAK kinase inhibitor for therapeutic applications.